1. Field of the Invention
The present invention relates generally to a method for treating multiple sclerosis (MS), and for reducing flu-like symptoms generally associated with administration of interferons. In particular, the method uses a fast-titration escalating dosing regimen of intramuscularly administered interferon. The invention also relates to titration packaging to promote compliance with the dosage titration.
2. Description of Related Art
Multiple sclerosis (MS) is a chronic neurological and inflammatory disorder of the central nervous system, marked by focal autoreactive T-cell and macrophage infiltration through the blood brain barrier that lead to demyelination, and axonal and neuronal loss. In people affected by MS, patches of damage called plaques or lesions appear in seemingly random areas of the CNS white matter. At the site of a lesion, a nerve insulating material, myelin, is lost in demyelination. Inflammation, demyelination, oligodendrocyte death, membrane damage and axonal death all contribute to the symptoms of MS.
Although MS has an unknown etiology, the classical hypothesis is that MS is a T helper 1 (TH1)-cell mediated autoimmune disease. Development of lesions is characterized by accumulation of activated microglia and macrophages. Acute plaques are characterized by blood brain barrier damage, infiltration by activated CD4+ T cells and clonotypic CD8+ T cells that recognize CNS autoantigens, and the presence of reactive astrocytes and proliferating oligodendrocytes. Pro-inflammatory cytokines, e.g. interleukin 12 (IL-12) and tumour-necrosis factor-a (TNF-a), are also present. There is further evidence that other adaptive immune cells (e.g. TH17 cells and peripheral B lymphocytes) and innate immune cells (dendritic cells, natural killer T cells and resident microglia) play a role in MS pathogenesis.
Relapse-remitting MS, the most common form of the disease, is characterized by multiple exacerbations over time. Exacerbations are attacks on vision, motor, sensory, and sphincter control and cognitive processes. Patients with relapse-remitting MS do not completely recover from these exacerbations and accrue neurologic disability with each subsequent exacerbation.
Natural human fibroblast interferon-beta (IFN-β) was the first drug to treat relapse-remitting MS. IFN-β has immunomodulatory effects, which include modulating cytokine levels (e.g., inducing Th1 (T-helper 1) related cytokines and Th2 related cytokines), inhibiting T-cell activation and proliferation, inhibiting transmigration of autoreactive T cells into the CNS, increasing T cell apoptosis, and reducing expression of molecules required for antigen presentation. IFN-β has well-established clinical effects and studies evidence that IFN-β works against multiple sclerosis through immunomodulation.
There are currently two different recombinant interferon-beta treatments for MS: interferon beta-1a (IFN-β1a) and interferon beta-1b (IFN-β1b). IFN-β1a and IFN-β1b are two distinct molecules with different recommended dosages, routes of administration and dosing intervals. IFN-β1a is a 166 amino acid glycoprotein with a predicted molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence is identical to that of natural human interferon beta. IFN-β1b has 165 amino acids and an approximate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material. IFN-β1b is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The specific activity of IFN-β1a and IFN-β1b are different and based on different World Health Organization (WHO) reference standards of recombinant interferon beta and different assays used to measure activity.
Current IFN-β1a treatments include Avonex®, CinnoVex™, Rebif®, and Resigene. Current IFN-β1b treatments include Betaseron® in the US and Betaferon® in Europe, and Extavia®. Avonex® and CinnoVex™ are administered intramuscularly, while the other interferon treatments for MS are administered subcutaneously.
Although there is a difference in specific activity between the two types of interferons, IFN-β1a and IFN-β1b share similar side effect profiles. For example, a common adverse event associated with interferon therapies are flu-like symptoms that develop within a few hours after administration and subside within 24 hours. Flu-like symptoms associated with administration of interferons include fever, muscle aches (myalgia), chills, sweating, fatigue, headache, and malaise. The exact mechanism for the development of flu-like symptoms is not well understood but occurs among patients taking interferons irrespective of disease state. It has been postulated that interferons stimulate the sub-thalamic nucleus, thus affecting temperature, as well as local cytokines resulting in other symptoms.
Generally, the flu-like symptoms will significantly decrease after 2-3 months. However, flu-like symptoms associated with interferon administration at the beginning of treatment can be a significant barrier to the initiation or maintenance of MS therapy, even before the onset of any therapeutic benefit. Use of an escalating dosing regimen (also known as dose titration) has become a routine practice for the administration of interferon therapies to manage side effects at the initiation of therapy. The goal of dose titration is to improve the acceptance and adherence of therapy and, thus, impact long-term health benefits for patients with multiple sclerosis. Currently, there are only two interferon-beta products, Betaseron® and Rebif®, that provide dose titration instructions in their labels. Both Betaseron® and Rebif® are administered subcutaneously.
The Betaseron® (10/07) label includes titration instructions for subcutaneous administration of IFN-β1b over a six-week period, with full dose beginning in week 7:                Weeks 1-2—¼ of a dose (0.0625 mg/0.25 ml)        Weeks 3-4—½ of a dose (0.125 mg/0.5 ml)        Weeks 5-6—¾ of a dose (0.1875 mg/0.75 ml)        Week 7—full dose (0.25 mg/1 ml)The Betaseron® label indicates dose titration may reduce flu-like symptoms. The European Betaferon® label (1-8-24) includes titration instructions for subcutaneous administration over a three week period, with full dose beginning in week 4:        Week 1—¼ of a dose (0.062 5mg/0.25 ml)        Week 2—½ of a dose (0.125 mg/0.5 ml)        Week 3—¾ of a dose (0.1875 mg/0.75 ml)        Week 4—full dose (0.25 mg/1 ml)Although the European Betaferon® label has a three week titration period with ¼ dose increments, the label recommends dose titration at the start of treatment in order to increase tolerability and to reduce side effects, only generally, at the start of therapy. Unlike the US Betaseron® label which indicates a 6 week titration period and the possibility of a reduction in flu-like symptoms, the 3 week titration period of the European Betaferon® label is silent with respect to treating flu-like symptoms. Two clinical studies reveal that ¼ dose increments over a three-week period do not provide a significant reduction in flu-like symptoms in comparison to slow titration regimens.        
Rice et al (Rice G P A, Ebers G C, Lublin F D, Knobler R L. Ibuprofen Treatment versus Gradual Introduction of Interferon beta-lb in Patients with MS. Neurology 1999;52:1893-1895) evaluated the effectiveness of dose titration in combination with ibuprofen in reducing the flu-like side effects of Betaseron® administered subcutaneously in 49 patients with Relapsing-Remitting and Secondary Progressive Multiple Sclerosis (RR and SPMS). This was a randomized, open-label, study that compared patients who did not titrate Betaseron® but took ibuprofen prophylaxis (Group A), to those who titrated Betaseron® with (Group B) and without Ibuprofen treatment (Group C). Group A received 8 million IU (MIU) of Betaseron® every second day (the standard dose) during weeks 0-4. Groups B and C each received Betaseron® according to the titration schedule starting at 2 MIU (25% of the standard dose) and increased at increments of 2 MIU (25% of the standard dose) during weeks 0-4. During weeks 0-4, 11% (2 out of 18) of Group A patients developed flu-like symptoms, 6% (1 out of 6) of Group B patients developed flu-like symptoms, and 40% of Group C patients developed flu-like symptoms (Table 1 of Rice et al.). The differences in incidence of flu-like symptoms between the group receiving ibuprofen treatment alone (Group A) and the group receiving dosage escalation and ibuprofen treatment (Group B) does not appear to be significant.
Moreover, Rice et al. reported that 5 (three from Group A, one from Group B, and one from Group C) of the 49 patients (10%) in the study experienced difficulty while escalating the dose of IFN-β1b, and these patients required either dosage reduction or a delay in the escalating schedule.
This was common practice according to Bayas et al. (Bayas A and Rieckmann P. Managing the Adverse Effects of Interferon-β Therapy in Multiple Sclerosis. Drug Safety 2000 Feb: 22 (2):149-159). Bayas et al. described dose titration for administration of IFN-β1b (which is only administered subcutaneously) where treatment began at 20 to 25% dose for 1 week, increased to 50% dose the second week, and if treatment was tolerated, increased to full dose. According to Bayas et al., interferon-β dosage should be reduced or kept at the same level for a longer time until improved drug tolerability allows an increase. Walther et al. (Walther E U, Hohlfeld R. Multiple Sclerosis Side Effects of Interferon beta Therapy and their Management. Neurology 1999; 53:1622-1627) recommended one dose reduction (between 25-50%) that should be maintained, rather than escalated, for 4-6 weeks. Thus, it was common practice to err on the side of an extended titration schedule.
Wroe (Wroe S J. Effects of dose titration on tolerability and efficacy of interferon beta-lb in people with multiple sclerosis. J Int Med Res 2005; 33:309-18) evaluated whether a slower, four-stage, 4 week titration to a final dose of 250 μg subcutaneous IFN-β1b might improve tolerability over a more rapid two-stage, 2 week titration in patients with relapsing-remitting MS over a 3-month period. In the slow-titration group, IFN-β1b was subcutaneously administered, initially at 62.5 μg (¼ dose) every other day for 9 days, and then at ¼ dose increments (125 μg and 187.5 μg, respectively) on days 11 and 21, and a full dose (250 μg) beginning on day 31 (i.e. in the middle of week 5) for the remainder of the 3-month treatment. See FIG. 1 of Wroe et al. In the fast-titration group, IFN-β1b was subcutaneously administered, initially at 125 μg (½ dose) every other day for 2 weeks and then at full dose for the remainder of the 3-month treatment. One of the primary adverse events assessed was flu-like symptoms. Wroe reported no noticeable differences with respect to the occurrence of adverse events between the two treatment groups, e.g., the incidence rates of flu-like symptoms were similar in the slow—(32.4%) and rapid titration (41.9%) groups (FIG. 3 of Wroe et al). Wroe concluded that a rapid-titration regimen (½ dose increments, with a full dose beginning in week 3) results in a quicker onset of clinical benefit and slow titration (¼ dose increments, with a full dose beginning in the middle of week 5) showed a non-significant reduction in flu-like symptoms compared to the rapid-titration regimen.
The Rebif® label includes titration instructions for subcutaneous administration of IFN-β1a three times per week over a 4-week period, with full dose administered in week 5:                Weeks 1-2—⅕ of a dose—subcutaneous injection 3×/week                    (titration dose for 33 μg=4.4 μg)            (titration dose for 44 μg=8.8 μg)                        Week 3-4—½ of a dose—subcutaneous injection 3×/week                    (titration dose for 33 μg=11 μg)            (titration dose for 44 μg=22 μg)                        Week 5—full dose—subcutaneous injection 3×/weekThe European Rebif® label recommends a gradual increase during a 4 week period to reduce adverse reactions. The ⅕ dose during the first two weeks serves the purpose of allowing tachyphylaxis to develop, thus reducing side effects. Both the US and European labels are silent with respect to treating flu-like symptoms associated with administration of interferon-beta. All of the products and clinical studies discussed thus far relate to subcutaneous administration of IFN-β1a or IFN-β1b.        
Brandes et al. (Brandes D W, Bigley K, Hornstein W, Cohen H, Au W, Shubin R. Alleviating Flulike Symptoms with Dose Titration and Analgesics in MS Patients on Intramuscular Interferon beta-la Therapy: a pilot study. Curr Med Research and Opinions 2007; 23:7:1667-1672), appears to be the first to investigate dose titration of intramuscular administration (IM) of IFN-β1a. Brandes et al. evaluated the effectiveness of dose titration in combination with acetaminophen or ibuprofen in reducing the flu-like side effects of Avonex® (IFN-β1a) in 47 patients with relapsing-remitting multiple sclerosis.
The Brandes et al. study was a multi-site, randomized, open-label, 12-week study. Group 1 patients received (IM) IFN-β1a at a dose of 30 μg once weekly with no titration. Groups 2 and 3 received (IM) IFN-β1a at ¼ dose during weeks 1 and 2, ½ dose for weeks 3 and 4, ¾ dose at weeks 5 and 6, and a full dose (30 μg) for weeks 7-12. Groups 1 and 2 received acetaminophen 650 mg 1 hour before each (IM) IFN-β1a injection, then every 4 hours as needed. Group 3 received ibuprofen 400 mg 1 hour before each (IM) IFN-β1a injection, again at 6 hours following injection, then every 6 hours as needed. Flu-like symptoms were recorded at three time points: baseline (first dose of analgesic, 1 hour pre-injection); Time A (second dose of analgesic, 4 hours post-injection); and Time B (12-15 hours post-injection).
Brandes et al. found that one-quarter titration (Groups 2 and 3) significantly reduced the proportion of patients with a mean increase of ≧2 from baseline in flu-like symptom score compared with no titration only at 4 hours post-injection during the first two weeks (FIG. 1A of Brandes et al., p=0.015 indicated with *). There was no significant difference between the one-quarter titration (Groups 2 and 3) and no titration (Group 1) at 4 hours during weeks 3-12 as the dose was increased. These data suggested that a ¼ dose escalation does not reduce flu-like symptoms, suggesting that further prolonged titration, i.e., an even slower titration, would be necessary.
Also, there was no significant difference between the one-quarter titration (Groups 2 and 3) and no titration (Group 1) at 12-15 hours during any week, including the first two weeks. These data suggested that initiating (IM) IFN-β1a injection with a ¼ dose had limited effects in reducing flu-like symptoms because the ¼ dose only delayed the onset of flu-like symptoms and only did so during the first two weeks.
Frohman et al (Frohman E et al. Disease-Modifying Therapy in Multiple Sclerosis: Strategies for Optimizing Management. Neurologist 2002;8:227-236) in a comprehensive review of MS therapy management, recommends initiating treatment during the tapering phase of a steroid regimen and applying a fractionated dosing scheme in patients treated with either Avonex®, Rebif® or Betaseron® in combination with a nonsteroidal anti-inflammatory agent. In particular, patients were started at 25% of the recommended dose and dosages were increased by 25% increments weekly to every other week. Frohman et al. describes the 25% dose as “a dose usually associated with minimal to no side effects” given that interferon-related side effects are dose-response related. Significantly, Frohman et al. states, “If patients experience severe and limiting side effects as the dose is increased, we will generally prolong titration, escalating by the same increment every 2 to 4 weeks. With this approach, we have had very few patients fail drug initiation.” Thus, Frohman teaches to err on the side of an extended titration schedule.
It is therefore desirable to provide a method for further reducing flu-like symptoms associated with intramuscular interferon administration, which will promote compliance and continuation of interferon therapy for MS.